. Amyloid-β peptide induces mitochondrial dysfunction by inhibition of preprotein maturation. Cell Metab. 2014 Oct 7;20(4):662-9. Epub 2014 Aug 28 PubMed.


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  1. I’m always encouraged to see investigators consider the possibility that mitochondria may play a role in AD. Over the past decade, data has accumulated from a number of labs that Aβ localizes to mitochondria not only in transgenic animals and in vitro systems, but also in brains from human AD subjects. Based on this, more and more people are wondering whether mitochondria may mediate the toxic effects of Aβ and thereby play an important role in AD neurodegeneration. I’m sure that to many investigators an additional attractive feature of this view is that it is consistent with the amyloid cascade hypothesis. Under this scenario Aβ is still the upstream problem in AD, but you need to explain why and how it causes neurodegeneration, and mitochondria provide that explanation.

    This paper is consistent with this view.  From a molecular biology perspective it is a very impressive study.  The demonstration that mitochondrial protein presequence processing and peptide turnover can be functionally coupled is simply beautiful.  Showing that Aβ, when added to the systems studied, perturbs mitochondrial protein processing and induces protean mitochondrial changes further establishes a potential link back to AD.

    While I have no concerns about the experimental data, the authors do not discuss data that indicate mitochondrial function in AD subjects is also altered outside the brain, for example in platelets and fibroblasts.  Does Aβ also account for that biochemical phenomenon?  They also do not touch on the cybrid literature, which suggests AD-specific mitochondrial functional changes can perpetuate in cell culture independent of the addition of exogenous Aβ. 

    I don’t think this study is necessarily inconsistent with a mitochondrial cascade hypothesis that presumes mitochondrial dysfunction precedes Aβ production in AD.  I would also point out that the physiologic role of intracellular Aβ (or extracellular Aβ, for that matter) is poorly understood.  In this spirit, data from this paper could be consistent with the existing hypothesis that considers the possibility that one physiologic role Aβ plays is to essentially turn off or destroy dysfunctional mitochondria.

    Interpretative issues aside, I think this study does a very good job of justifying mitochondria as an AD therapeutic target.  If for no other reason, based on this and the basic biology it reveals, this is a very valuable paper.

  2. This is a very interesting and important paper. There is substantial evidence for mitochondrial deficits in Alzheimer's disease, however, the mechanism has been obscure. We and others found evidence for an impairment of cytochrome oxidase in both postmortem brain tissue and in platelets. However, it has been difficult to find mitochondrial DNA mutations to account for this observation. In collaboration with Doug Wallace, we found increased mutations in non-coding control regions of the mitochondrial genome, but sequencing of the three mtDNA encoded COX subunits has not shown point mutations. The possibility of another mechanism therefore has been important to explore. This paper presents a potential mechanism.

    As the authors report, most nuclear encoded mitochondrial proteins are imported with presequences that are then cleaved off by proteases in the mitochondrial matrix. The authors show that the peptidasome Cym1/PreP plays a critical role in this processing. It has also been shown that there are abnormalities in mitochondrial respiration and increased ROS production in AD. It is also known that PreP can degrade Aβ. The authors showed that Aβ impairs the processing of the presequence peptides. They showed that processing of COX4 preprotein is impaired in mitochondria from PS2/APP mice. They then showed that the presequence peptide for MDH2 accumulates in mitochondria from AD brains. In yeast mitochondria deficient in cym1, ATP production was impaired, respiration decreases, and ROS increased.

    I think that these findings may tie together a number of observations in AD, and link mitochondrial dysfunction to effects of Aβ in mitochondria. There is evidence for this, particularly in synaptic mitochondria. I think it would have been nice if the authors had showed that the impaired processing of COX4 presequence led to an impairment of COX activity in the transgenic mice and postmortem AD tissue. Nevertheless, these are important observations that suggest a mechanism by which Aβ can directly contribute to mitochondrial dysfunction in AD.  

  3. Mitochondrial dysfunction is one of the most prominent and earliest deficits in Alzheimer's and likely plays a critical role in the pathogenesis of this disease. This interesting study demonstrated a novel mechanism by which Aβ causes mitochondrial dysfunction. Most mitochondrial proteins are encoded by the nucleus and are imported into mitochondria with the guidance of presequence that is cleaved and degraded after successful import. First, the authors used a yeast model to elegantly demonstrate a functional coupling between mitochondrial presequence processing and the presequence peptide turnover. They went on to convincingly show in yeast that Aβ could specifically inhibit the presequence peptide degradation, which in turn impaired the cleavage of presequence. Mitochondrial deficits ensued.

    More importantly, the authors confirmed that the processing of the presequence of several nuclear-encoded mitochondrial proteins was indeed impaired in brain mitochondria from AD patients, where mitochondrial Aβ is abundant, suggesting that such a mechanism is probably of pathophysiological relevance to human disease.

    It was unexpectedly found almost a decade ago that Aβ is present in mitochondria. In fact, Aβ could be imported through the mitochondrial import machinery and likely impairs mitochondrial function, at least in part, through specific interactions with several mitochondrial proteins such as ABAD and cypD. Mitochondria even have their own enzyme (e.g., matrix prepeptidase) to degrade Aβ. This study adds a new twist to the mitochondrial Aβ story in that it suggests this exact Aβ-degrading enzyme in mitochondria is also a target of the toxic effect of mitochondrial Aβ. This not only leaves the mitochondrial level of Aβ unchecked, but also results in dysfunctional mitochondrial preprotein maturation and an imbalance in the organelle proteome, which could collectively contribute to the pleiotropic mitochondrial deficits in AD.  This study suggests that mitochondrial matrix prepeptidase could be a critical target for preventing the toxic effects of mitochondrial Aβ. 

    While there is no question that this is a very intriguing idea and the authors convincingly demonstrated it in the yeast model, we need to be cautious about its implication for human disease without a similar mechanistic study in mammalian systems. Moreover, this study raises additional questions. For example, impaired processing of the mitochondrial presequence in AD brain mitochondria appeared limited to only several, instead of the full spectrum, of the mitochondrial proteins as would be expected due to the universal effect of mitochondrial Aβ. What causes such selectivity? What is the functional importance of such selectivity? Is such selective vulnerability sufficient to cause overall imbalance in mitochondrial proteome and pleotropic mitochondrial deficits in AD? One should also bear in mind that Aβ may impact mitochondrial function through other cytosolic mechanisms such as calcium-induced abnormal changes in mitochondrial dynamics.

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